None.
(1) Field of the Invention
The present invention relates to a method for strengthening collagen in collagenous tissue which uses the controlled application of heat to induce shrinkage or contraction of the collagen in the tissue and a cross-linking means which cross-links the shrunken collagen in the tissue thereby stabilizing the strengthened, collagenous tissue. In particular, the present invention relates to an in vivo method for treating joint instability problems, controlled manipulation of skin structure and properties, and other problems involving collagen-containing tissues. The present invention further relates to an in vitro method for stabilizing collagenous tissue for use in vivo or in vitro. Further, the present invention relates to a method for treating collagenous tissue and testing the strength and stability of the treated tissue.
(2) Description of Related Art
Glenohumeral instability caused by shoulder capsular redundancy, glenohumeral joint laxity, and excessive joint volume, for example, is a problem affecting approximately 8% of the population. Kinematically, the problem may be defined as the inability to maintain the humeral head (the ball) centered in the fossa (the socket) caused by the pathological redistribution of the forces that keep the joint in equilibrium.
Redistribution of the forces are generally initiated by soft tissue problems. These can occur from a single acute event that disrupts the capsule, recurrent microtrauma that damages the biological microstructure of the joint capsule or a traumatic ligamentous laxity. The result is that the soft tissue allows for excessive motion of the joint surfaces in directions not normally permitted by the ligaments or capsule surrounding the joint.
This problem is generally seen in athletes and the young. In the milder cases, symptoms include shoulder fatigue, weakness and pain while repetitive dislocation and subluxation and even the loss of motion are indicative of more severe cases.
Currently applied treatments for glenohumeral instability include closed techniques, open techniques, and arthroscopic techniques. Closed techniques which are based on exercise depend on strengthening the muscle group that surrounds the shoulder joint. In addition to relatively long treatment period (6 to 12 months), the high reoccurrence rate limits their application as a stand alone method (Hayashi et al., Am. J. Sports Med. 25: 107-112 (1997)). The success in treatment of mild cases is only about 20% (Burkhead et al., J. Bone Surg. 74A: 890-896 (1992).
Open techniques generally involve operative procedures and the method applied depends on the type of instability, i.e., anterior, posterior or multidirectional. It has been reported that approximately 300 different operative procedures have been applied for the surgical management of instability (Zayne et al., Clin. Sports Med. 14: 863-883 (1995)). In addition to being technically difficult, these operations which are performed for the capsule shift or repair are generally known to result in pain and have the potential to reduce range of motion and even cause loss of motion, nerve injury and osteoarthritis (Bana et al., Sports Med. Arthroscopy Rev. 1: 242-248 (1993); Bigliani, Techn. Orthop. 3: 36-45 (1989); Jobe, Techn. Orthop. 3: 29-35 (1989)). Only 30% of patients undergoing surgical operations for glenohumeral instability appear to achieve their pre-injury function.
Arthroscopic techniques generally pose less risk of neuromuscular injury and typically involve a shorter rehabilitation period compared to open techniques. While arthroscopic techniques have less risk of neuromuscular injury and require a shorter rehabilitation period than other techniques, these techniques require extreme technical expertise and are very much dependent on the skill of the surgeon. Furthermore, in many cases, the repair effected by arthroscopic techniques is short-term since reoccurrence rates as high as 50% have been observed. As such, alternatives to the foregoing techniques are highly desirable.
Recently, arthroscopic thermotherapy has begun to be applied for the treatment of glenohumeral instability problems. The therapy aims to reduce the excessive capsular volume and ligamentous laxity by heating the articular surfaces of the glenoid and the humeral head, a method otherwise referred to herein as heat assisted capsular shift procedure. Arthroscopic thermotherapy techniques for contracting collagen fibers in soft tissue to increase rigidity of the tissue have been the object of several U.S. Patents.
U.S. Pat. No. 5,591,157 to Hennings et al. discloses an apparatus and method for tightening the tympanic membrane by using a laser to apply heat to the collagen fibers of the membrane. The heat causes the collagen fibers to contract which tightens the membrane.
U.S. Pat. Nos. 5,569,242 and 5,458,596 to Lax et al. discloses an apparatus and method for strengthening the collagenous tissue in the joint to stabilize the joint by the controlled contraction of the collagen tissue. The apparatus provides thermal energy to the soft tissue which causes the collagen fibers to contract or shrink thereby improving the stability of the joint.
Although results of short term follow ups show that arthroscopic thermotherapy is promising with relative few side effects, questions about the long term effect remain unanswered. Improved range of motion of the repaired shoulder, accelerated patient healing, as well as lower recurrence rates are the major advantages of this therapy. The disadvantages are the time dependent decrease of tissue stiffness, over-stiffening or excessive drop in tissue strength in cases of overexposure to heating, and the trend for relaxation of the treated tissue back to its untreated length. This kind of response has also been observed in most of the research done using animal models (Chen and Humphrey, J. Biomechanics 31: 211-216 (1998); Chen et al., IEEE Trans. Biomed. Eng. 45: 1234-1240 (1998); Shaefer et al., Am. J. Sports Med. 25: 841-848 (1997)). Time-dependent changes in the mechanical properties and behavior of the treated tissue are thought to be the major reason for recurrence and thus, failure of the therapy in the long run. A further disadvantage with currently proposed arthroscopic thermotherapy is that the success of the therapy completely depends on subjective parameters such as the visual perception, experience, and judgment of the surgeon. Thus, while arthroscopic thermotherapy appears to be an advancement in the art, understanding the phenomena involved in tissue response is incomplete and because of recurrence, improvements are clearly needed.
There are other methods known in the art for modifying collagen. For example, chemical modification of collagen films and collagenous tissues using cross-linking agents such as glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, hexamethylene diisocyanate and diphenylphosphorylazide which induce inter/intramolecular bonds have been used for fixation in histological examinations (Simionescu et al., J. Biomed. Mater. Res. 25: 1495-1505 (1991)), controlled drug release (Gohel and Amin, J. Controlled Release 51: 115-122 (1998)), delaying the in vivo degradation of (Lynn et al., J. Biomed. Mater. Res. 24: 1185-1201 (1990)), and suppressing the recipient immune response (Gade et al., J. Biomed. Mater. Res. 25: 799-811 (1991)) to soft tissue xenografts like porcine heart valves and arteries. On the macro scale, the effects of these modifications are known to be pronounced with respect to viscoelastic behavior and mechanical properties like stiffness and toughness (Finger et al., Arch. Ophthalmol. 105: 716-718 (1987); Lee et al., J. Biomed. Mater. Res. 28: 981-992 (1994); Davidson, Conn. Tissue Res. 18: 293-305 (1989); Naimark et al., Biorheology 35: 1-16 (1998)) as well as with respect to the denaturation temperature (Ruijrok et al., J. Mater. Sci. Mater. Med. 5: 80-87 (1994); Horgan et al., Arc. Biochem. Biophys. 281: 21-26 (1990); Moore et al., J. Biomed. Mater. Res. 32: 209-214 (1996); Gavilanes et al., Conn. Tissue Res. 13: 37-44 (1984)).
Chemical modification of collagen fibers using cross-linking agents has been the object of several U.S. Patents. U.S. Pat. No. 5,567,806 to Abdul-Malak et al. discloses using cross-linking agents in the manufacture of suturable, biocompatible slow-resorbing membranes which can be used for guided tissue regeneration. U.S. Pat. No. 5,264,551 to Petite et al. discloses a process for cross-linking collagen in articles intended for implantation in a patient using diphenylphosphorylazide which provides the ability to modulate the biodegradability of the collagen depending on the degree of cross-linking. U.S. Pat. No. 4,544,638 to Siegel discloses a process for introducing cross-links in the helical domain of collagen using pyridoxal 5-phosphate and copper or iron. The process is designed to reintroduce into processed collagen the native cross-linking which provides the native collagen its high tensile strength and resistance to degradation and resorption.
However, chemical cross-linking has not been used in the treatment of glenohumeral instability problems or loose skin problems, and in particular, chemical cross-linking has not been used in conjunction with thermotherapy.
The present invention provides a method for treating collagenous tissue wherein both the mechanical properties and the stability of the collagenous tissue are improved over current methods. In one embodiment, the present invention provides an improved arthroscopic thermotherapy method wherein a curing solution containing one or more cross-linking agents is used in combination with the controlled heat administration to the collagenous tissue or after the controlled administration of heat to the collagenous tissue. When heat is applied to the collagenous tissue, the native cross-links in the collagen are disrupted which causes the collagen to denature and thus to contract and shrink. A cross-linking means is provided which cross-links the contracted collagen thereby maintaining the collagen in the contracted form. Cross-linking the contracted collagen improves the mechanical properties of the collagenous tissue because it abrogates the time-dependent decrease of tissue stiffness and/or tensile strength and by modifying the viscoelastic response so as to prevent the contracted collagen to relax back to its untreated length. In the manner supra, the present invention improves the safety and reliability of thermotherapy procedures, in particular, Heat-Assisted Capsular Shift procedures which are used to repair joint injuries of the shoulder, elbow, wrist, hand, spine, neck, hip, knee, and ankle. In an other embodiment, the present invention provides a method for treating loose skin by tightening up the skin with heat treatment to the collagen therein followed by treatment with a cross-linking means which stabilizes the tightened skin. The method is useful for removing wrinkles and sagging skin caused by old age, and sagging skin caused by over-stretching or prolonged stretching of the skin.
Thus, the present invention provides a stabilizing treatment of collagenous tissue in vivo in a mammal which comprises providing an energy source to the collagenous tissue to heat the collagenous tissue, heating the collagenous tissue for a time sufficient to contract collagen comprising the collagenous tissue, and treating the contracted collagenous tissue with a non-toxic cross-linking means which cross-links the contracted collagen wherein the cross-linked contracted collagen stabilizes the collagenous tissue. In particular, the collagenous tissue comprising internal body parts selected from the group consisting of shoulder, elbow, wrist, hand, spine, neck, hip, knee, and ankle, or the collagenous tissue comprising skin.
In the method of the present invention, the cross-linking means is a chemical cross-linking agent or a photo-fixing means with or without a dye. Preferably, the chemical cross-linking agent is selected from the group consisting of glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, hexamethylene diisocyanate, diphenylphosphorylazide, and mixture of pyridoxal-5-phosphate and cupric or ferrous ion. Further, in the method of the present invention, the energy is preferably provided by a source selected from the group consisting of a laser, an electrode which provides a radiofrequency energy, ultrasound, an alternating magnetic field, microwaves, and heated aqueous solution.
The present invention further provides a system for a stabilizing treatment of collagenous tissue in vivo which comprises a heating means for heating the collagenous tissue so that collagen comprising the collagenous tissue is contracted, and a dispensing means for introducing a non-toxic cross-linking means into contact with the collagenous tissue so that the contracted collagen is stabilized.
Further still, the present invention provides an in vitro or in vivo method for treating tissue, in particular collagenous tissue, to stabilize the collagen therein which comprises providing heat to tissue containing the collagen wherein the collagen is contracted because of being heated, and treating the contracted collagen with a cross-linking means which cross-links the contracted collagen so that the contracted collagenous tissue is stabilized.
In particular embodiments of the system for treatment and the in vivo or in vitro method of treatment supra, the treatment is to the collagenous tissue comprising internal body parts selected from the group consisting of shoulder, elbow, wrist, hand, spine, neck, hip, knee, and ankle, or the collagenous tissue comprising skin. In an embodiment further still, the treatment is accomplished arthroscopically.
In the system for treatment or the in vitro or in vivo method of treatment supra, the cross-linking means is a chemical agent which is preferably selected from the group consisting of glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, hexamethylene diisocyanate, diphenylphosphorylazide, and mixture of pyridoxal-5-phosphate and cupric or ferrous ion or a photo-fixing means with or without a dye, and it is preferable that the heating means is selected from the group consisting of a laser, an electrode which provides a radiofrequency energy, ultrasound, alternating magnetic field, microwaves, and heated aqueous solution.
The present invention further provides an apparatus for treatment of tissue to stabilize collagen therein which comprises a holding means for mounting the tissue to be treated, a heating means for heating the tissue to contract the collagen therein, and a dispensing means for introducing a cross-linking agent into contact with the contracted collagen which cross-links the collagen, thereby stabilizing the contracted collagen in the tissue which increases its mechanical strength.
Further still, the present invention provides a system for testing stabilizing treatments on collagenous tissue which comprises: an apparatus comprising a holding means for mounting the tissue to be treated, an energy means for heating the tissue to contract collagen therein, a dispensing means for introducing a cross-linking means into contact with the contracted collagen which cross-links the collagen thereby stabilizing the contracted collagen in the tissue, and a testing means for testing mechanical properties of the tissue before, during and after treatments.
In particular embodiments of the apparatus or system of the present invention, the dispensing means provides the cross-linking agent to the tissue in a field and the heating means is selected from the group consisting of a laser, an electrode which provides a radiofrequency energy, ultrasound, alternating magnetic field, microwaves, and heated aqueous solution. In particular embodiments, the cross-linking means is a chemical agent which is preferably selected from the group consisting of glutaraldehyde, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide, hexamethylene diisocyanate, diphenylphosphorylazide, and mixture of pyridoxal-5-phosphate and cupric or ferrous ion or a photo-fixing means with or without a dye.
The apparatus and system supra are particularly useful for treating or testing collagenous tissue comprising internal body parts selected from the group consisting of shoulder, elbow, wrist, hand, spine, neck, hip, knee, and ankle, or the collagenous tissue comprising skin.
Objects
Therefore, it an object of the present invention to provide a method and system for providing increased mechanical strength and stability of collagenous tissue. In particular, it is an object of the present invention to provide a method that enables the long-term repair of joint problems and loose skin problems.
These and other objects will become increasingly clear with reference to the following preferred embodiments, examples and drawings.